(1) Field of the Invention
SUMMARY: This invention relates to novel compounds having an inhibitory activity against 12-lipoxygenase.
More particularly, this invention is related to (1) aryl aliphatic acids or derivatives thereof having an inhibitory activity against 12-lipoxygenase, of the following general formula: EQU R--(C.sub.x --C.sub.y)--(C.sub.m H.sub.2m)-B--C(R.sup.1).sub.2 --Ar--(C.sub.n H.sub.2n)--COOR.sup.2
including the acid, pharmaceutically acceptable salts thereof and esters and (2) process for the preparation of them, and (3) 12-lipoxygenase inhibiting agents containing them as an active ingredient.
(2) Prior Art
Lipoxygenases are the enzymes related to the oxidative metabolic pathway of unsaturated fatty acids. 5-,8-, 11-, 12- and 15-Lipoxygenases are rather well characterized examples of these enzymes. A particular lipoxygenase oxidizes a particular position of arachidonic acid to produce a particular metabolite. For example, 5(X)-lipoxygenae produces 5-HETE (5(S)-5-hydroxyeicosa-6(E), 8(Z)-14(Z)-tetraenoic acid or LTs (so called leukotrienes) through 5-HPETE (5(S)-5-hydroperoxyeicosa-6(E), 8(Z), 11(Z), 14(Z)-tetraenoic acid). In spite of being found in mammalian tissue the role of 12-lipoxygenase is not well known.
12(S)-HETE (12(S)-hyroxyeicosa-5(Z), 8(Z), 10(E), 14(Z)-tetraenoic acid), a metabolite of arachidonic acid, is produced by 12-lipoxygenase and possesses a variety of biological characteristics, e.g. antagonism of LTB.sub.4 and enhancement of the enzyme activity of 5-lipoxygenase. It is thought that 12-lipoxygenase is involved in inflammation and immunity. Further, it is also thought that lipoxygenases are closely related to ischemic heart diseases and ischemic brain diseases.
It has been reported that 12-HETE induces a chemotactic reaction of smooth muscle cells in rat (Atherosclerosis, 44, 339, (1982)). It was thought that such chemotactic action of 12(S)-HETE produced by 12-lipoxygenase in plasma platelets might be related to the induction of arteriosclerosis.
Recent studies have shown that some types of cancer cells can induce aggregation of plasma platelets. Cancer cells activate plasma platelets, in such a way that metabolites of arachidonate are released. Among these metabolites, a considerable amount of 12-HETE was detected (Cancer Res., 47, 6751, (1987)).
It has also been found that a process of cancer metastasis involves adhesion of a cancer cell(s) to subendothelial matrices through receptors, the expression of which is enhanced by 12-HETE (Cancer Res., 49, 1029, (1989)). Various inhibitors are known as shown by (1) Hamberg, M., Samuelson, B. Proc. Natl. Acad. Sci. U.S.A., 71, 3400 (1974); and (2) Honn, K. V., Grossi, I. M., Steinert, B. W., Chopra, H., Onoda, J., Nelson, K. K., Taylor, J. D., Advances in Prostaglandins, Thromboxane, and Leukotriene Research, Vol. 19, Raven Press, Ltd., New York, 439-443 (1989).
A 12-lipoxygenase inhibitor inhibits the production of 12-HETE by 12-lipoxygenase. Therefore, 12-lipoxygenase inhibitors may be useful for the treatment and/or prevention of inflammation, cancer metastasis, immune diseases, psoriasis, arteriosclerosis and/or ischaemic cardiovascular diseases.